Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
  • C07D263/62—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems having two or more ring systems containing condensed 1,3-oxazole rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/10—Oxygen atoms
  • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
  • C12P17/14—Nitrogen or oxygen as hetero atom and at least one other diverse hetero ring atom in the same ring
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the invention relates to a process for the preparation of Diarylcycloalkylderivaten of the general formula (I). Furthermore, the present invention relates to novel intermediates which are formed in the process according to the invention.
• cis-1,3-cyclohexanediol is first alkylated either with a protective group (benzyl or silyl) or already with one of the two substituents of the target molecule, wherein forming the racemic mixture of the corresponding monoalkylated cis compound.
• This intermediate is in turn reacted either with an acyl donor, whereupon this monoalkylated and monoacylated intermediate, which is also present as a racemate, is separated into two fractions via enzymatic ester cleavage and subsequent chromatography, from which the two enantiomers of the target molecule can each be synthesized in separate reaction routes.
• the racemic monoalkylated intermediate can be separated into two fractions by enzymatic ester formation and subsequent chromatography, from which in turn the two enantiomeric forms of the target molecule can be synthesized in two separate batches.
• a disadvantage of this method is, in particular, that despite the avoidance of chiral chromatography, first a racemic intermediate product is formed from which forcibly the two enantiomeric forms of the target molecule are obtained. If the synthesis variant is used via the protective group introduced first, the benzyl-containing protective groups must be removed by hydrogenation. In this hydrogenation, the first substituent of the target molecule already attached to the corresponding intermediate can to a certain extent also be removed again, which leads to a yield loss. Silyl-containing protective groups are removed with fluoride, which also leads to further side reactions in the other substituents of the corresponding intermediate compounds and is therefore to be avoided.
• trans -1,3-diacetoxycyclohexane becomes ( 1R , 3R ) -3-acetoxy-cyclohexan-1-ol (60% yield) with 27% enantiomeric excess and cyclohexane-1,3-diol (70% yield).
• This method is therefore not suitable for producing an acceptable enantiomeric excess or enantiomerically pure cis -1S-Acytoxycyclohexan-3R-ol.
• the object underlying the present invention is to provide a novel process for preparing PPAR activators of the general formula (I), which does not have the disadvantages of the processes known from the prior art.
• the ring A or the substituents X and Y are hereinafter referred to as simple radicals (alkyls or alkenyls), even if - depending on the approach - in Case of the ring A is a name as alkane or alkene (ring A as the basic fragment of the formula (I)) or as alkylene or alkenylene is conceivable.
• a suitable enantiomeric excess should be an enantiomeric purity (ee) of greater than 50% ee, preferably greater than 90% ee, more preferably greater than 95% ee, even more preferably greater than 98% ee, much more preferably greater than 99% ee and particularly preferred greater than 99.5% ee be understood.
• ee enantiomeric purity
• steps a1) and / or a2) are carried out in the presence of lipase B from Candida antarctica.
• the process according to the invention has the advantages that the use of suitable enzymes already introduces the chiral information into the respective precursors at the beginning of the process, as a result of which these precursors are already enantioselective in a suitable, if appropriate, extremely high Enantiomeric excess (enantiomeric purity> 99% ee) present. Consequently, the desired enantiomers of the compounds (I) can be prepared enantioselectively in a suitable, possibly even in extremely high enantiomeric excess (enantiomeric purity> 99% ee).
• the chiral information (in some cases> 99% enantiomeric purity of the precursors) which is already stable at the beginning of the synthesis remains due to the stable basic group Z3 despite two alkylation steps to the chiral PPAR activator of formula (I) whose enantiomeric purity is therefore also> 99%. ee is.
• the enzymes used in the process according to the invention make it possible to use the starting materials used not only in the form of the respective pure cis isomer but also as cis / trans mixtures without adversely affecting the enantiomeric purity of the intermediates or of the target molecule.
• trans starting compounds can be easily removed by purification of the intermediates, for example by extraction, due to the protective group used. Additional purification steps, for example with chromatography, are not required for this purpose.
• lipase B from Candida antarctica used in step a1) of the process according to the invention enantiomeric purities of> 99% ee can already be achieved in solution at a conversion of> 90% without the need for recrystallization.
• step i) is carried out in the presence of a porcine pancreas lipase, a Burkholderia cepacia lipase, a Burkholderia species lipase, a Pseudomonas cepacia lipase or a Pseudomonas species lipase.
• the compounds (V) are prepared by step a), with several options being open for this purpose.
• the compounds (V) have been known for some time in the literature. For example, from K. Dimroth et al., Ber. (1942), 75B, 322-6 the monoacetate of acyloxycyclohexanols described. In the publication by T. Hirata et al. Cited above. also describes how various cis-1S-acyloxycyclohexan-3R-ole can be isolated by chiral chromatography. The main problem is to be seen in the separation of the compound (V) into the individual enantiomers, which is very difficult in practice, since chiral chromatography has to be used for this purpose.
• the individual enantiomers of compounds (V) can be prepared by enzymatic acylation from compounds (X).
• the compounds (X) can be used either as cis / trans isomer mixtures or as pure cis isomers and are commercially available in these forms from various suppliers (for example from Merck, Fluka or Aldrich). If the compounds (X) are used in the form of the pure cis isomer, this has the disadvantage that they must first be isolated from the corresponding cis / trans mixtures or that the pure cis isomers are more expensive.
• the enzymatic acylation can be carried out in the context of the process according to the invention in the presence of various enzymes (for example lipases) with an acyl donor.
• a single acyl donor or a mixture of several acyl donors can be used.
• the reaction can be carried out either without additional organic solvent (Example 1) or with an additional organic solvent (Example 2).
• Suitable organic solvents for this are in principle all common organic solvents such as toluene, chlorinated hydrocarbons or ethers, preferably methyl tert-butyl ether. However, the reaction can not be carried out in water.
• Suitable acyl donors are all chemical compounds which can form an acid-stable protecting group Z1 or Z2.
• Examples include carboxylic acid ester.
• vinyl esters such as vinyl acetate, isopropenyl acetate, vinyl laurate or vinyl butyrate, more preferably vinyl acetate or isopropenyl acetate.
• the cis-monoacyl compound (V) is preferably formed starting from a cis / trans isomer mixture of the compound (X), while the diacyl compound (IX) is obtained only as a by-product.
• the direct reaction (enzymatic acylation) of a compound of the formula (X) to give a compound of the formula (V) is preferably carried out in the presence of the lipase B from Candida antarctica. Particularly preferably, this reaction is carried out in the presence of a lipase selected from Chirazyme L2 lyo., Chirazyme L2 cf C2 or Chirazyme L2 cf C3.
• a lipase selected from Chirazyme L2 lyo., Chirazyme L2 cf C2 or Chirazyme L2 cf C3.
• the resulting in this reaction reaction mixture of compounds of formulas (IX) and (V) can optionally be separated by extraction, distillation or chromatography.
• the separation at this point is not absolutely necessary because the by-product compound (IX) in the subsequent step b) can not be provided with a protective group Z3.
• the by-product (IX) is deprotected twice in step c) of the process according to the invention and optionally removed by extraction in the workup of the compound (II).
• a similar consideration can be made for the unreacted educt (X) that either already in this process step by extraction, distillation or chromatography can be separated or in the workup of the compounds (II) or (IX).
• lipase B from Candida antarctica can be used in the enzymatic acylation also a lipase of pig pancreas, a lipase from Burkholderia cepacia, a lipase from Burkholderia species, a lipase from Pseudomonas cepacia or a lipase from Pseudomonas species.
• both compounds (IX) and (V) are formed from the starting material (X).
• the monoacyl compounds (V) are present in the undesired trans form, while the compounds (IX) also formed are surprisingly present predominantly as cis-diacyl.
• These cis-diacyl compounds (IX) can be converted by enzymatic desymmetrization (enzymatic hydrolysis) to the desired cis-enantiomers of the compound (V) as explained below.
• the reaction of a compound (X) by enzymatic acylation to give a compound (IX) mainly as a cis isomer is preferably in the presence of a lipase selected from a porcine pancreas lipase, a Burkholderia cepacia lipase, a Burkholderia species lipase, a lipase from Pseudomonas cepacia or a lipase from Pseudomonas species.
• a lipase selected from a porcine pancreas lipase, a Burkholderia cepacia lipase, a Burkholderia species lipase, a lipase from Pseudomonas cepacia or a lipase from Pseudomonas species.
• the lipase is selected from a porcine pancreas lipase, a Burkholderia cepacia lipase, a Burkholderia species or Pseudomonas cepacia lipase. More preferably, the lipase is selected from Chirazyme L1 lyo, Chirazyme L1 cf, Chirazyme L7 lyo or Lipase PS. More preferably, the lipase is selected from Chirazyme L1 lyo., Chirazyme I1cf or Chirazyme I7 lyo. The assignment of the aforementioned Enzyme trade names to the NCBI accession number can be found in Table 1.
• the trans compound (V) formed as undesired by-product in this synthesis route is separated from the compound (IX) by extraction, distillation or, if appropriate, chromatography, provided the starting material (X) is cis / trans mixture is used.
• this work-up step is omitted if the compound (X) is used as a pure cis isomer.
• the possible separation of the by-product (V) is carried out by extraction. Since the subsequent enzymatic desymmetrization of the compound (IX) is carried out with another enzyme and in the aqueous phase, the enzyme used in the enzymatic acylation should be removed beforehand, for example by filtration. The enzyme is preferably removed prior to separation of the monoacyl compound (V-trans).
• the compounds (IX) can be obtained from the compounds (X) by enzymatic acylation as mentioned above.
• the compounds (X) may also be directly reacted with the above acyl donors (in the absence of enzymes) to the compounds (IX).
• This reaction has been known for a long time and is referred to as chemical acylation, but not stereoselectively (Examples 3 and 4).
• the chemical acylation can be carried out, for example, with acetic anhydride / 4-dimethylaminopyridine (4-DMAP), triethylamine (TEA) in dichloromethane.
• the chemical acylation can be either with a single acyl donor or a It is preferred to use a single acyl donor so that in compound (IX) the substituents Z1 and Z2 have the same meaning.
• the compounds (IX) can be reacted with water to give the compound (V) in the presence of an enzyme which provides a suitable enantiomeric excess of the compound (V).
• the enzyme used is preferably lipase B from Candida antarctica. This reaction is particularly preferably carried out in the presence of a lipase selected from Chirazyme L2 lyo., Chirazyme L2 c.f. C2 or Chirazyme L2 c.f. C3 performed. This reaction must be carried out in aqueous solution, the exclusive use of organic solvents is not suitable here. Surprisingly, the trans-diacyl compound (IX) is not converted by the lipase B from Candida antarctica.
• enantiomerically pure compounds are understood as meaning compounds which have a purity of> 98% (ee> 98%), preferably> 99% (ee> 99%), particularly preferably> 99.5% (ee> 99, 5%).
• the great advantage of using lipase B from Candida antarctica is that irrespective of whether a single acyl donor or a mixture of acyl donors is used, compound (V) is always formed in enantiomerically pure form.
• the protecting groups Z1 and Z2 are independently an acid-stable protecting group.
• the protective groups Z1 and Z2 preferably have the same meaning.
• Z1 and Z2 are preferably -C (O) -R, R is optionally substituted alkyl or aryl, for example C 1 -C 6 -alkyl or phenyl.
• Z1 and Z2 are more preferably independently of one another -C (O) - (C 1 -C 3 -alkyl), particularly preferably -C (O) -CH 3 .
• the lipase B from Candida antarctica can be used both in its non-immobilized form (Chirazym L2) and in its immobilized forms (cf, cfC2, cfC3, manufacturer: Roche Diagnostics).
• the lipase B from Candida antarctica is also from other manufacturers such. Novozymes (Novozym 435 as Immobilisat) available. Alternatively, dissolved lipase B from Candida antarctica, e.g. Novozym CALB L or Novozym 525 F can be used after immobilization of the enzyme.
• the compound (V) is reacted in the presence of an acid catalyst with a compound which can form a base-stable and acid-labile protecting group Z3 to the compound of the formula (VIII).
• acidic catalysts for example, inorganic acids, toluenesulfonic acid, pyridinium paratöluolsutfonat or acidic ion exchangers such as Amberlyst H15 can be used.
• pyridinium para-toluenesulfonate is used for this purpose.
• the protecting group Z3 present in compound (VIII) is a base-stable and acid-labile acetal or ketal protecting group.
• Z3 is more preferably tetrahydropyranyl or methoxyisopropyl, most preferably tetrahydropyranyl.
• 3,4-dihydro-2H-pyran is preferably suitable.
• One equivalent of the compound (V) is reacted with 1 to 10 equivalents of the compound forming the base-stable and acid-labile protecting group Z3, preferably 1.1 to 1.4 equivalents.
• the acid catalyst is usually used at 0.01 to 1 equivalent, preferably 0.05 to 0.1 equivalent.
• the reaction temperature is usually 20 to 80 ° C, preferably 50 to 60 ° C.
• Step b) like all other steps of this process, is usually carried out at atmospheric pressure.
• Suitable solvents for step b) are organic solvents such as chlorinated hydrocarbons, carboxylic acid esters such as ethyl acetate, carboxylic acid amides such as N-methylpyrrolidone, ether compounds such as diethyl ether or methyl tert-butyl ether, aromatic hydrocarbons such as chlorobenzene or toluene.
• organic solvents such as chlorinated hydrocarbons, carboxylic acid esters such as ethyl acetate, carboxylic acid amides such as N-methylpyrrolidone, ether compounds such as diethyl ether or methyl tert-butyl ether, aromatic hydrocarbons such as chlorobenzene or toluene.
• 3,4-dihydro-2H-pyran itself can be used as a solvent.
• Preferred solvent is toluene.
• water or alcohols are not suitable solvents, since they react, for example, with 3,4-dihydro-2H
• the compound (VIII) is reacted in the presence of a nucleophile to the compound (II).
• This reaction referred to as deacylation, may be described as a nucleophile for example, an alkali metal or alkaline earth metal alkoxide, preferably sodium methoxide are used. 0.1 to 10 equivalents of nucleophile are used per one equivalent of compound (VIII), with catalytic amounts of 0.1 to 0.3 equivalents being preferred.
• the reaction temperature is usually 10 to 80 ° C, preferably 15 to 25 ° C.
• This deacylation step can be carried out in all organic solvents which do not react with the nucleophile (sodium methoxide), for example aromatic hydrocarbons, alcohols, chlorinated hydrocarbons.
• toluene is preferred as the solvent, since it is also possible to extract with toluene in the preceding process step, so that no solvent change is necessary in the deacylation, with toluene, the alkylation can also be carried out in the following step d).
• the compound (II) can be distilled for purification, but this is not absolutely necessary.
• Suitable bases B1 are tertiary alkaline earth metal alkoxides, tertiary alkali metal alkoxides, alkaline earth amides, alkali metal amides, alkaline earth metal silazides, alkali silicides or alkali metal hydrides. Primary or secondary alkoxides, however, are not suitable.
• Preferred bases B1 are potassium tert-butylate (KOtBu), tertiary isopentylate, lithium diisopropylamide or potassium bis (trimethylsilyl) amide. Particularly preferred are potassium tert-butoxide or potassium bis (trimethylsilyl) amide.
• Suitable organic solvents are organic aprotic solvents, for example ether compounds (diethyl ether, methyl tert-butyl ether), carboxamides (N-methylpyrrolidone), aromatic hydrocarbons (chlorobenzene or toluene), preference being given to toluene.
• the reaction is usually carried out at 20 to 80 ° C, preferably at 50 to 60 ° C.
• 1 equivalent of the compound (II) is usually reacted with 1 to 3 equivalents of alkylating agent (compounds (VI) and (VII)), preferably 1.1 to 1.3 equivalent alkylating agents.
• the base B1 is used with 1 to 3, preferably 1.5 to 2 equivalents.
• alkylating reagents of the formulas (VI) and (VII) are commercially available or can be prepared by methods known from the literature.
• Z4 and Z5 are independently a leaving group. All common leaving groups can be used here, preference being given to chlorine or bromine.
• Preparation processes for compounds of the formula (VI) can be found, for example, in US Pat WO 03/020269 or in the international application WO 2004/076390 or in The Chemistry of Heterocyclic Compounds (Ed .: A. Weissberger, EC Tayl or): Oxazoles (Ed .: IJ Turchi ), b).
• step d) with the compound (VI) or the compound (VII) is alkylated depends on the target molecule (I) desired enantiomer.
• the compounds (II) are reacted with the compound of the formula (VI), especially when the ring A is cis-1,3-cyclohexyl.
• the compound (IIIa) is converted to the compound (IVa) or the compound (IIIb) to the compound (IVb), wherein the respective reaction is carried out with an alcohol in the presence of an acidic catalyst.
• Suitable acid catalysts are the same compounds that are already listed in step b), wherein the Selection of the acidic catalyst in step b) and e) can be carried out independently.
• Suitable alcohols are preferably primary alcohols, in particular methanol. This step is carried out at a temperature of 20 to 80 ° C, preferably 45 to 55 ° C.
• Suitable solvents are the organic aprotic solvents already mentioned under step d), preferably toluene. The selection of the solvent in step d) and e) can be carried out independently.
• One equivalent of the compounds (III) is reacted with from 0.01 to 10 equivalents of acid, preferably 0.05 equivalents of, for example, hydrochloric acid.
• the alcohols used are used here with 1 to 3 equivalents.
• the compound (IV) formed in this step can be distilled for purification. If this compound is crystalline, purification by crystallization is preferred, less preference is given to purification by means of chromatography, since an excessively high use of solvent is necessary for this purpose.
• step f) The compound (IVa) is reacted in step f) with the compound (VII) or the compound (IVb) with the compound (VI) to the compound (Ia) in the presence of the base B1.
• the selection of the base B1 is carried out independently of step d), but preferably the same base as in step d) is used. In principle, it is also possible to use the same solvents as in step d), the choice of solvent also being independent of step d).
• chlorobenzene can also be selected in this second alkylation step, with chlorobenzene being preferred here because of a larger conversion compared to toluene.
• the quantitative ratios of starting compounds, alkylating agents and base B1 used correspond to those of step d).
• the reaction is usually carried out at -30 to + 20 ° C, preferably at -5 to + 5 ° C.
• step f) corresponds to the compound (I).
• the compound (Ia) is replaced by Hydrolysis or hydrogenolysis in the compound (I) transferred.
• the hydrolysis can be carried out by common methods both in the basic (R6 is preferably n-alkyl) or in the acidic (R6 is preferably tert-butyl). If R 6 is a benzyl radical, the compound (I) is preferably obtained by a hydrogenolysis by methods known to the person skilled in the art.
• metal hydroxides such as, for example, alkali metal or alkaline earth metal hydroxides are used in a ratio of 1 to 10 equivalents to the compound to be saponified.
• Suitable solvents include water, alcohols or other organic solvents such as ether compounds (diethyl ether, methyl tert-butyl ether), carboxamides (N-methylpyrrolidone) or aromatic hydrocarbons.
• ether compounds diethyl ether, methyl tert-butyl ether
• carboxamides N-methylpyrrolidone
• aromatic hydrocarbons tertiary butanol is used.
• the reaction temperature is 20 to 100 ° C, preferably 65 to 75 ° C.
• the desired chiral PPAR activator of formula (I) is released in an enantiomeric purity of> 99% ee.
• organic solvents such as aromatic solvents, preferably toluene, ethyl acetate or n-butyl acetate, or optionally with carboxylic acid esters, alkyl ethers or alkyl alcohols are carried out. This recrystallization can also be carried out after step e).
• steps b) to g) are all carried out in the same solvent, toluene is preferably used for this purpose.
• This preferred embodiment of the process according to the invention is particularly suitable for the preparation of compounds of the general formula (I) in which the ring A is cyclohexyl, where the X-containing and the Y-containing substituent of formula (I) in cis-1, 3 position to the cyclohexyl fragment and the carbon atom of the ring A, which is substituted with the Y-containing substituent, has R configuration.
• compound (V) can be prepared by enzymatic acylation with a suitable lipase from compound (X) as described above, but compound (IX) is preferred as a starting point.
• compound (IX) can be prepared by enzymatic acylation with a suitable lipase from compound (X) or preferably via chemical acylation from compound (X).
• a reaction sequence to be used as typical, including the precursors, is shown by way of example below for these preferred embodiments.
• compounds of formula (I) can be prepared in which the ring A is cyclohexyl, the two X- and Y-containing substituents are arranged in the cis-1,3-position to the ring A and the carbon atom of the ring A substituted with the Y-containing substituent has R configuration.
• the process conditions described in the respective synthesis steps, for example for the acids, bases or solvents used, also apply to the other compounds of the formula (I) in which the ring A is not restricted to cis-1,3-cyclohexane derivatives.
• 1,3-Cyclohexanediol can be converted either directly by an enzymatic acylation to cis-1S-acyloxy-cyclohexane-3R-ol (Vi) or by chemical acylation via 1,3-diacyloxy-cyclohexane (IX-i) as an intermediate.
• a chemical and in the enzymatic acylation preferably only one of the above-described acyl donors is reacted so that in formula (IX-i) the acid-stable protecting groups Z1 and Z2 have the same meaning.
• 1,3-Diacyloxy-cyclohexane is also commercially available as a cis-isomer (IX-1-cis) or as a cis / trans mixture (from Clariant).
• Cis-1,3-diacyloxy-cyclohexane or the cis / trans mixture (IX-i) is in this case by an enzymatic desymmetrization (enzymatic hydrolysis) as described above in the almost enantiomerically pure cis -1S-acyloxy-cyclohexan-3R-ol ( 99% ee) (Vi) converted.
• acidic catalysts such as inorganic acids, toluenesulfonic acid, pyridinium para-toluenesulfonate or acidic ion exchangers
• primary alcohols such as methanol, ethanol in the presence of acidic catalysts such as inorganic acids, toluenesulfonic acid, pyridinium para-toluenesul
• the hydrolysis step need no longer be carried out, because in this case the compound (1a)
• the hydrolysis can be carried out in acidic or basic form
• R6 tert-butyl
• the hydrolysis is preferably carried out in acid.
• the ring A is cis-1,3-cyclohexyl, wherein the carbon atom of the ring A having the OH substituent has R-configuration, and Z1 and Z2 are the same as -C (O) - (C 1 -C 3 alkyl).
• the trans isomer of the compound (IX) the trans isomer of the compound (V) or the cis isomer of the compound (IX).
• the ring A is cis-1,3-cyclohexyl, wherein the carbon atom of the ring A, which has the OH substituent, has R configuration, and Z1 and Z2 equal -C (O) - (C 1 -C 3 alkyl).
• the compounds of formulas (IIIa) and (IIIb) can be prepared according to steps a) to d) of the process according to the invention.
• the same statements apply as for the preparation of the compounds of formula (I).
• Retention times 24.4 min, derivative of cis -1S-acetoxy-cyclohexa-3R-ol with heptafluorobutyric acid; 25.2 min, derivative of cis -1R-acetoxy-cyclohexa-3S-ol with heptafluorobutyric acid;
• Candida antarctica fraction B Roche Diagnostics CAA83122; EP-A 287 634 Chirazyme L2 cf C2 Candida antarctica, fraction B Roche Diagnostics CAA83122 Chirazyme L2 cf C3 Candida antarctica, fraction B Roche Diagnostics CAA83122 Chirazyme L7 lyo. porcine pancreas Roche Diagnostics P00591 Lipase PS Pseudomonas cepacia Amano Enzymes EP-A 331,376 Lipase AH Pseudomonas sp. Amano Enzymes
• the cis-monoacetates are preferably formed. Furthermore, the enzymes Chirazyme L7 lyo., Chirazyme L1 lyo., Chirazyme L1 cf, Lipase PS and Lipase AH surprisingly catalyzed the formation of cis-diacetate from cis-cyclohexane-1,3-diol with simultaneously high conversion, whereas the trans- Compound predominantly converted only to trans-monoacetate (Table 2).
• the resulting from the respective enzymes mixtures of monoacetate and diacetate can then be separated, for example by extraction or distillation. This also succeeds in the separation of cis-1,3-diacetoxycyclohexane from commercially available cis / trans mixtures of cyclohexane-1,3-diol.
• Table 2 1) enzyme 2) Sales 3) monoacetate 4) diacetate 5) proportion of cis diacetate from 4) Chirazyme L7 lyo.
• cis / trans-cyclohexane-1,3-diol is prepared by simple acylation with acetic anhydride or with acetyl chloride, as for example from Organikum page 405-7, 16. Auflage 1986 VEB German publishing house of the sciences (Berl in) are converted to cis / trans-1,3-diacetoxy-cyclohexane.
• Cis-cyclohexane-1,3-diol is prepared by simple acylation with acetic anhydride or with acetyl chloride, as for example from Organikum page 405-7, 16th edition 1986 VEB German publishing house of the sciences (berl in), are converted to cis-1,3-diacetoxy-cyclohexane.
• the removal of the pyridinium para-toluenesulfonate by a filtration is not absolutely necessary because in the subsequent deacetylation excessively used sodium methoxide neutralizes the acidic salt pyridinium para-toluenesulfonate and the deacetylation is not affected thereby.
• the resulting filtrate is used without further purification in the subsequent deacetylation to cis-3R- (O-tetrahydropyranyl) cyclohexane-1S-ol.
• the toluene solution of cis -1S-acetoxy-3R- (O-tetrahydropyranyl) -cyclohexane from Example 5 is mixed with 115 ml of methanol and with 7.48 g (0.3 eq.) Of 30% sodium methoxide-methanol solution to Reaction brought.
• the quantitative deacetylation can be monitored by GC analysis.
• the workup can be carried out either by method A) or B):
• the reaction mixture is mixed with 600 ml of water.
• the toluene phase is extracted 3 times with 600 ml of water.
• the aqueous phases are combined, saturated with NaCl and extracted three times with 600 ml of toluene each time.
• the remaining cis-1,3-cyclohexanediol derivatives incurred during the process ie those starting materials, by-products or precursors which do not correspond to example 6 or the by-product formed with 2 THP protective groups, remain as water-soluble compounds in the aqueous phase.
• the organic phases are combined and concentrated under vacuum.
• Cis-3- (O-tetrahydropyranyl) cyclohexane-1S-ol is obtained as a colorless oil of> 97% purity and> 96% yield based on cis-1S-acetoxycyclohexan-3R-ol.
• the thus prepared cis-3R- (O-tetrahydropyranyl) cyclohexane-1S-ol has a molecular weight of 200.28 (C 11 H 20 O 3 ); MS (EI): 199 (M - H + ).
• Cis -3- (O-tetra-hydro-pyranyl) -cyclohexan-1-S-ol is obtained as a colorless oil with a purity> 95% and a yield of> 95% based on cis -1S-acetoxy-cyclohexane-3R- ol received.
• the cis-3- (O-tetrahydro-pyranyl) -cyclohexan-1S-ol prepared in this way has a molecular weight of 200.28 (C 11 H 20 O 3 ); MS (EI): 199 (M - H + ).
• Example 7 Alkylation with 4- (chloromethyl) -2- (4-fluorophenyl) oxazole to give cis -1S- (2- (4-fluoro-phenyl) -oxazol-4-yl-methoxy) -3R-O-tetra- hydropyranyl-cyclohexane
• the combined organic phases can also be used without further purification in the subsequent cleavage of the tetrahydropyranyl protective group to cis -3S- (2- (4-fluoro-phenyl) -oxazol-4-yl-methoxy) -cyclohexan-1-R-ol ,
• Example 10 Saponification and Release by Acidification of the Carboxyl Function to Cis -2- (3S- (2- (4-Fluorophenyl) -oxazol-4-ylmethoxy) cyclohexyl-1R-oxy-methyl) -6-methylbenzoic Acid
• the aqueous solution is mixed with 50 ml of acetone and acidified with 2M salsa acid to a pH 4-5.
• the solution is stirred at 0-5 ° C to give cis -2- (3S- (2- (4-fluorophenyl) -oxazol-4-yl-methoxy) -cyclohexyl-1R-oxy-methyl) -6-methyl benzoic acid is formed as a white crystalline solid (purity> 95%) which can be separated by filtration.
• the combined aqueous phases are adjusted to pH 8 with 35 ml of 2 M HCl, and 21 ml of n-butyl acetate are added. With a further 10.5 ml of 2M HCl, the 2-phase mixture is adjusted to pH 4 and heated to 90 ° C. The phases are separated in a preheated separating funnel. The organic phase is heated with activated charcoal to 90 ° C and filtered. The filtrate is cooled to room temperature to give cis -2- (3S- (2- (4-fluorophenyl) -oxazol-4-yl-methoxy) -cyclohexyl-1R-oxy-methyl) -6-methylbenzoic acid as a white solid (purity > 90%) crystallized.
• Example 11 Alkylation with 4- (chloromethyl) -2- (3-methoxyphenyl) -5-methyloxazole to give cis -1S- (2- (3-methoxyphenyl) -5-methyloxazol-4-ylmethoxy) -3R-O -tetrahydropyranylcyclohexan
• Example 13 Alkylation with 2- (bromomethyl) -6-methyl-benzoic acid methyl ester to give cis -2- (3S- (2- (3-methoxyphenyl) -5-methyloxazol-4-yl-methoxy) -cyclohexyl-1R- oxymethyl) -6-methylbenzoate
• the reaction mixture is extracted after cooling to room temperature with 30 ml of water.
• the chlorobenzene solution is then extracted again with 80 ml of water.
• the combined aqueous phases are mixed with 40 ml of methylene chloride and adjusted to pH 2 with 10 ml of 2M HCl. After vigorous stirring, the phases are separated and the organic phase concentrated in vacuo. The residue is taken up in diisopropyl ether and worked up analogously as in Example 14a above.
• Example 6 with 4- (chloromethyl) -5-methyl-2-p-tolyl-oxazole in the presence of, for example, alkali and alkaline earth bases, preferably in the presence of potassium tert-butoxide or potassium bis ( trimethylsilyl) -amide, reacted to Example 15.
• Example 15 with methanol in the presence of acidic catalysts such as inorganic acids, toluenesulfonic acid, pyridinium para-toluenesulfonate, Amberlyst H15, preferably with inorganic acids in Example 16 transferred.
• acidic catalysts such as inorganic acids, toluenesulfonic acid, pyridinium para-toluenesulfonate, Amberlyst H15, preferably with inorganic acids in Example 16 transferred.
• 2-Bromomethyl-6-methylbenzoyl bromide reacts with alcohols such as methanol (MeOH), tert-butanol (tBu-OH) or benzyl alcohol (Bn-OH) to Example 17a, Example 17b or Example 17c.
• Alcohols such as methanol (MeOH), tert-butanol (tBu-OH) or benzyl alcohol (Bn-OH) to Example 17a, Example 17b or Example 17c.
• Example 16 is used with Example 17a, Example 17b or Example 17c in the presence of, for example, alkali and alkaline earth bases, preferably in the presence of potassium tert-butoxide, alkylated to Example 18a, Example 18b and Example 18c, respectively.
• Example 18a is saponified with metal hydroxides such as alkali and alkaline earth metal hydroxides, preferably sodium and potassium hydroxides, in suitable solvents such as water, alcohols or organic solvents, preferably in ethanol or isopropanol. After acidification, for example with organic or inorganic acids, preferably with inorganic acids, the desired chiral PPAR activator Example 19 is isolated. Example 19 is also obtained by ester cleavage with acidic catalysts such as inorganic acids or trifluoroacetic acid (TFA), preferably hydrochloric acid or trifluoroacetic acid, from Example 18b.
• metal hydroxides such as alkali and alkaline earth metal hydroxides, preferably sodium and potassium hydroxides
• suitable solvents such as water, alcohols or organic solvents, preferably in ethanol or isopropanol.
• acidic catalysts such as inorganic acids or trifluoroacetic acid (TFA), preferably hydrochloric acid or trifluoroacetic acid
• Example 18c is converted by hydrogenolysis with a heterogeneous catalyst, preferably a noble metal catalyst, and more preferably a palladium catalyst in Example 19.
• Example 19 is isolated in an optical purity of> 99% ee, requiring neither chiral nor achiral chromatography for purification. The purification is carried out by crystallization of Example 16 and the PPAR activator Example 19, for example from an organic solvent, preferably from diisopropyl ether.
• Example 15 Alkylation of cis -3R- (O-tetrahydropyranyl) -cyclohexan-1S-ol with 4- (chloromethyl) -5-methyl-2-p-tolyl-oxazole to give cis- 1S- (2-p-tolyl- 5-methyl-oxazol-4-yl-methoxy) -3R-O-tetrahydropyranyl-cyclohexane
• reaction mixture is stirred for 10 minutes at room temperature before adding a solution of 111 g (501 mmol) of 4- (chloromethyl) -5-methyl-2-p-tolyl-oxazole in 1.5 L of tert-butyl methyl ether.
• the reaction is stirred at 35 ° C. until complete conversion (HPLC). An aliquot of the reaction mixture is washed with water, dried over magnesium sulfate and then completely concentrated in vacuo.
• Example 16 Cleavage of the THP-protecting group of cis -3S- (2-p-tolyl-5-methyl-oxazol-4-yl-methoxy) -3R-O-tetrahydropyranylcyclohexane to cis -3S- (2-p-tolyl- 5-methyl-oxazol-4-yl-methoxy) cyclohexane-1R-ol
• Example 17a Synthesis of 2-bromomethyl-6-methyl-benzoic acid methyl ester from 2-bromomethyl-6-methyl-benzoylbromide
• tert-butyl 2-bromomethyl-6-methylbenzoate is obtained as an almost colorless oil of 93% purity and having a molecular weight of 284.04 (C 13 H 17 BrO 2 ), MS (ESI): 302, 1 [M + NH 4 ] + .
• Example 18a Alkylation of cis -3S- (2-p-tolyl-5-methyl-oxazol-4-yl-methoxy) -cyclohexan-1R-ol with 2-bromomethyl-6-methyl-benzoic acid methyl ester to 2-methyl-6 - [(1R, 3S) -3- (5-methyl-2-p-tolyl-oxazol-4-yl-methoxy) -cyclohexyloxymethyl] -benzoic acid methyl ester
• reaction is stirred for 1 hour at temperatures between 25 ° C and 30 ° C and is quenched by the addition of 500 mL hydrochloric acid (0.5 molar). After separation of the aqueous phase, the organic phase is washed three times with 300 ml of water. Subsequently, the solvent is completely removed in vacuo.
• Example 18b Alkylation of cis -3S- (2-p-tolyl-5-methyl-oxazol-4-yl-methoxy) -cyclohexan-1R-ol with tert-butyl 2-bromomethyl-6-methylbenzoate 2-methyl-6 - [(1R, 3S) -3- (5-methyl-2-p-tolyl-oxazol-4-yl-methoxy) -cyclohexyloxymethyl] benzoic acid tert-butyl ester
• Example 18c Alkylation of cis -3S- (2-p-tolyl-5-methyl-oxazol-4-yl-methoxy) -cyclohexan-1R-ol with 2-bromomethyl-6-methyl-benzoic acid benzyl ester to 2-methyl-6 - [(1R, 3S) -3- (5-methyl-2-p-tolyl-oxazol-4-yl-methoxy) -cyclohexyloxymethyl] -benzoic acid
• the 2-methyl-6 - [(1R, 3S) -3- (5-methyl-2-p-tolyl-oxazol-4-ylmethoxy) -cyclohexyloxymethyl] benzoic acid prepared by the various variants has a molecular weight of 449.55 (C 27 H 31 NO 5 ); MS (ESI): 450.29 [M + H] + .
• Example 20 Alkylation of cis -3S- (2- (4-fluorophenyl) -oxazol-4-yl-methoxy) -cyclohexan-1R-ol with 2-bromomethyl-6-methyl-benzoic acid tert-butyl ester to give cis - 2- (3S- (2- (4-fluorophenyl) -oxazol-4-yl-methoxy) -cyclo-hexyl-1R-oxymethyl) -6-methylbenzoic acid tert-butyl ester
• Example 21 Cleavage of the tert-butyl ester of cis -2- (3 S - (2- (4-fluorophenyl) -oxazol-4-yl-methoxy) -cyclo-hexyl-1R-oxymethyl) -6-methylbenzoic acid tert butyl ester to cis -2- (3S- (2- (4-fluorophenyl) -oxazol-4-yl-methoxy) -cyclohexyl-1R-oxymethyl) -6-methylbenzoic acid

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